BTLA通过ASNA-1调节β细胞功能的机制研究

I型糖尿病（TIMD）是以胰腺β细胞分泌胰岛素严重不足导致的代谢紊乱性疾病。内质网应激(ERS)反应可引起β细胞凋亡及胰岛素分泌减少，促进TIMD的发生。ASNA-1可通过调控尾锚定蛋白的定向转运，抑制ERS并促进β细胞存活，但ASNA-1的调节机制尚未知。前期研究我们发现免疫辅助信号分子BTLA表达于β细胞并促进ASNA-1表达。BTLA-/-小鼠有高空腹血糖、低空腹血胰岛素等特征，提示BTLA可能通过促进ASNA-1改善β细胞功能，但机制未清楚。本研究拟使用WB等技术体外分析BTLA通过PI3K/Akt-STATs通路促进ASNA-1表达的分子机制；构建BTLAβ-/-小鼠，探讨BTLA对β细胞凋亡及功能的影响；最后使用抗体阻断BTLA信号，分析其对TIMD发展的干预效果。本研究将明确BTLA调控β细胞功能的分子机制，为TIMD的临床提供新策略。

Diabetes is a metabolic disorders disease characterized by chronic hyperglycemia, which effects human health seriously. Thus, controlling the occurrence and development and reducing complications are urgent. Endoplasmic reticulum stress (ERS) is associated with β-cell apoptosis and insulin secretion reduction, both of which are related to diabetes. ASNA-1 regulates ERS and β-cell function though the tail-anchored proteins. However, the mechanism of regulating ASNA-1 is unclear. Our preliminary research revealed that BTLA expressed in pancreatic β cells and binds to ASNA-1 directly. BTLA knockout mice showed a high fasting blood glucose, low fasting blood insulin and lack of glucose-stimulated insulin secretion, suggesting that BTLA may regulate insulin secretion through ASNA-1. In this study, we are going to construct BTLA-specific gene knockout in β cell mice to explore how BTLA regulates the function of β cells, and analyze the apoptosis of NIT-1 pancreatic cancer cells in vitro by WB and RNAi. In the last, we will block the BTLA signal with antibodies to explore the effects of BTLA on diabetes and insulin resistance. This research will clear how BTLA regulate the function mechanism of pancreatic β cell, which have a significant on the clinical treatment of diabetes and other diseases.